CB1 and CB2 are two cannabinoid receptors that belong to the GPCR family and have very different functions and distribution. While no x-ray structure is available for these receptors, various models have been described on the basis of the x-ray structure of rhodopsin, a GPCR belonging protein responsible of the light sensitivity in vision. Matsuda L A, Lolait S J, Brownstein M J, Young A C, Bonner T I, Structure of a Cannabinoid Receptor and Functional Expression of the Cloned cDNA, Nature 1990, 346:561-4. CB1 is abundantly expressed in the central nervous system and is most dense in the basal ganglia, cerebellum, hippocampus, and cortex and in the peripheral nervous system, it is expressed in such sites as the testis, eye, urinary bladder, and adipocytes. CB2 is mainly expressed in the immune tissues, in cells such as those in the thymus, marrow, spleen, pancreas, and in glioma and skin tumor cells. It was recently demonstrated that CB2 receptors and their gene transcripts are widely distributed in the brain. A third cannabinoid receptor seems to be present as some chemical analogues exhibit cannabinoid biological activity without activating CB1 and CB2. Di Marzo V, Bifulco M, De Petrocellis L, The Endocannabinoid System and Its Therapeutic Exploitation, Nat Rev Drug Discov 2004, 3:771-84.
Solubility is important for any oral solid dosage form of cannabinoid receptor modulating compounds, as the compounds must be released, dissolved in aqueous gastrointestinal media, traverse the endothelial barrier, and bypass various metabolic enzymes to reach systemic circulation and deliver a therapeutic effect. If the cannabinoid receptor modulating compound does not dissolve, it will be wasted, passing through the gastrointestinal tract without serving its intended pharmacological purpose. The development of effective oral dosage forms for poorly soluble compounds such as cannabinoid receptor agonists and antagonists therefore represents a significant challenge.
Bioavailability is a subcategory of absorption and is the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases, due to incomplete absorption and first-pass metabolism. Many cannabinoid receptor agonists are hydrophobic, and suffer from poor bioavailability when administered orally. Accordingly, there remains a need for improved formulations for oral administration of hydrophobic cannabinoid receptor agonists.